Electrophysiology screening technologies are important for drug discovery. They are advanced due to automated, high-throughput electrophysiology measurement systems with large capacity libraries for screening and obtaining data to support drug discovery programs.
Ion channels play a key role in regulating many types of tissue functions. Ion channels themselves are regulated by both trans-membrane cation and anion gradients and dynamic changes in membrane potential, and they generate current as a useful index of their activity.
A typical high-throughput electrophysiology measurement system for ion channel screening comprises multiple first compartments, each compartment containing an aperture (or multiple apertures) connecting the first compartment to a second compartment. Furthermore, each first compartment contains a first electrode and the second compartment contains a second electrode. The electrodes are connected to an electrical data acquisition system. The compartments are filled with aqueous electrolyte solutions (first and second solutions respectively), and a biological membrane is positioned in the apertures, separating the first and the second compartments. By applying an electrical voltage across the electrodes and measuring currents through the electrodes electrophysiological properties of the biological membrane can be studied.
It has been noted that the electrodes utilized in such systems may not have a stable, well-defined electrochemical potential. Each electrode may be prone to have an electrical voltage error or voltage offset, in the range of up to several tens of millivolts (mV). In addition, voltage errors (or voltage offsets) may result due to electrochemical gradients between the first and second solutions (known also as junction potentials) that may reach values of one hundred millivolts or higher.
The electrical data acquisition system may not function appropriately when it includes a large number of channels (for example, 384 channels) and utilizes inexpensive, small, and low-power components, which may also have a tendency for electrical voltage offsets (voltage errors). Electrical voltage offsets from all of the channels may substantially aggravate voltage errors that compromise data acquisition.
To compensate for such voltage errors compensating circuitry may be incorporated into the data acquisition systems. The compensation circuitry may contain programmable digital-to-analog converters (trim DACs, or tDACs), one tDAC for each electrode/data channel. The tDACs are programmed to compensate for the voltage offsets. However, the requirements for tDACs are such that they are difficult to satisfy in multi-channel systems. The tDACs should have a sufficient resolution and a large enough voltage range to fully compensate for the voltage offsets. With a large number of channels, the cost and complexity of offset-compensating tDACs can become significant, packaging can become difficult, and reliability can suffer.
Therefore, there is a need for an improved approach to screening ion channels using a high-throughput measurement system with voltage offset correction.